5-alpha-reductase converts testosterone into the most potent androgen, dihydrotestosterone (DHT). DHT is a testosterone metabolite via the 5AR enzyme in both males and females. Androgen receptors mediate endocrine processes such as male sexual differentiation of the fetus, muscle growth, anabolism, weight loss, libido, hair loss, and male urine flow. 5 alpha-dihydrotestosterone binds to the androgen receptor to regulate specific gene expression. DHT accumulates in prostate cells with age even as blood testosterone and DHT decline with age. Men suffering from prostate-related urinary symptoms have higher levels of dihydrotestosterone whereas blood testosterone level showed no effect on urinary tract symptoms. DHT affects both male and female alopecia and female hirsutism and poly cystic ovary syndrome (PCOS). PCOS is associated with enhanced androgen and cortisol metabolite excretion and increased 5 alpha-reductase activity and increased adrenal corticosteroid production. Male andropause with its decreased serum testosterone, typically below 300 ng/dL and lower, results in tissues starved of testosterone along with more conversion of existing testosterone to deleterious DHT. The male climacteric entails not only reduced blood testosterone, but an increased ratio of estrogens, FSH, LH and sex-hormone binding globulins.
Estrogens have an important role in the development and progression of benign prostate enlargement. The enzyme aromatase converts testosterone into estradiol. Estrogens can stimulate prostate growth, resulting in hyperplasia of the gland, stimulating proliferation of the stromal cells in the prostate gland that causes many urinary symptoms. Estradiol causes rapid proliferation of prostate stromal cell and anti-estrogen compounds block this undesirable affect. Prostate enlargement sufferers have significantly higher serum estradiol concentrations those without enlargement with 1.78 times higher incidence of urinary tract symptoms. Therefore DHT and estradiol are associated with highest levels of urinary tract symptoms in BPH patients. Estrogenic effects are common with many anti-BPH 5ARI formulations and are undesirable.
5-alpha-reductase inhibition therapies which reduce DHT are prudent. Inhibitors of 5-alpha-reductase are useful for the selective treatment of benign prostate hyperplasia, female PCOS, female hindradenitis ativa, female hirsuitism and male-impaired urine-flow. It is desirable to avoid affecting spermatogenesis, sexual behavior and smooth muscle growth that do not require the conversion of testosterone to 5-alpha-dihydrotestosterone. Testosterone therapy may contribute to increased DHT; therefore treatment of testosterone insufficiency with testosterone may exacerbate BPH. Many anti-DHT therapies are estrogenic.
BPH affects over 60% of men over the age of 50 causing urinary hesitancy, incomplete voiding, terminal dribbling, urgency, frequency and nocturia. Nocturia troubles 80% of men 60-80 years old and 90% of men over 80 years old. Stage I BPH involves obstructive and irritant symptoms. Stage II BPH begins when there is decomposition of the voiding mechanism, leading to residual urine of 100-150 ml and pollakisuria (increased frequency). In Stage III BPH, chronic and complete retention of urine or overflow incontinence causes reduction of renal function and uremia, a disease secondary to renal failure where nitrogenous waste products accumulate in the blood.
BPH-related urinary problems such as incontinence, the inability to control urination, affects some 5% of the population. The condition introduces profound psychological effects, sleep interruption and hygiene issues. Chronic lack of sleep imposes greater risk of other diseases such as cancer, heart attack, depression and inflammatory syndromes. Incontinence can affect both men and women. The standard medical treatments include physiotherapy, diapers, and treatment of both psychological and social problems. Overflow incontinence in males occurs secondary to hormonal imbalances causing narrowing of the urethra from a variety of causes including BPH.
Problems: Preferred anti-DHT treatments possess 5-alpha-reductase inhibition activities such that testosterone conversion to the more active dihydrotestosterone by 5-alpha-reductase is inhibited. Beyond highly potent 5 alpha-reductase inhibiting activity and safety, the preferred compounds would not trigger an estrogenic response at all or to any significant degree. Thus the compounds may simultaneously maintain testosterone receptor efficacy and/or whole-body androgenicity via non-DHT producing analogs, while treating excess DHT conditions in males, e.g. male urine flow impaired and the like and excess DHT conditions in females, e.g. hirsutism, and PCOS. Thus desirable androgenic effects are caused without any increase in either serum testosterone or creation of deleterious DHT. A non-testosterone androgenic receptor agonist which, because it does not increase serum testosterone, cannot be converted to deleterious DHT or lead to higher levels of DHT, would be of benefit to conditions, syndromes and diseases which are worsened by DHT such as pattern alopecia, benign prostatic hypertrophy, urinary obstruction in males, while at the same time testosterone agonism is needed. Accordingly, there is a demand for development of a novel anti-DHT which is completely free of any safety problems, which does not increase testosterone or estrogenic effects. Currently employed medicines as 5-alpha-reductase inhibitors have untoward side effects, either estrogenic, anti-androgenic or others, such as permanent erectile dysfunction with finasteride.
Anticholinergic agents are used as monotherapy or in combination with α1-adrenocepetor inhibitors for patients with storage disorders while phosphodiesterase 5 (PDE5) inhibitors are used for patients with lower urinary tract symptoms and concomitant erectile dysfunction. Examples of problems of current therapies which are primary pharmacological treatments such as alpha 1-adrenoreceptor inhibitors, 5-alpha-reductase inhibitors, anticholinergics and PDE-5 inhibitors.
Antiandrogenicity: Angelica Tenuissima, Artocarpin, Beta Sitosterol, Epicatechin, Epigallocatechin, Unsaturated Fatty Acids (GLA, Alpha-Linolenic Acid, Stearic Acid, Linolenic Acid, Linoleic Acid, Palmitoleic Acid, Oleic Acid, Palmitic Acid, Myristoleic Acid and Arachidonic Acid). Medium chain fatty acids such as those found in coconut and the kernel of many palm fruits have also been found to inhibit 5α-reductase. Finasteride, Perilla sikokiana (contains linoleic acid and linoleic acid), Pumpkin Seed Lipid Fractions, Serenoa Repens (the fruit of saw palmetto contains about 25% fatty acids consisting of capric, caprylic, lauric, palmitic, oleic, linoleic and linoleic acids in the form of fixed oils and campesterol, stigmasterol and beta-sitosterol), S. Flavescens. 
Estrogenicity: Biochanin-A, Daidzein, Pumpkin Seed Extract (contains lignin phytoestrogens secoisolariciresinol which is intestinally converted to enterodiol, a 5ARI type III), Serenoa Repens contains estrogenic 5ARI compounds. (Elghamry 1969), Solasodine, S. Flavescens is highly estrogenic, β-sitosterol and other plant phytosterols, Soy genistein and daidzein, Pygium africanum. Other: Flutamide (transaminase elevation, dry skin)
Erectile Dysfunction: cGMP phosphodiesterase inhibitors (PDE5 inhibitors) such as Sildenafil (WO 94/28902) are orally effective agents useful for impotence. 70% of the population over age 50 suffers loss of libido or erectile dysfunctions, often associated with heart or kidney disease. Drugs used include testosterone, VIP, prostaglandin derivatives PGEs and cardiovascular agents such as phenoxybenzamine, phentolamine and papaverine. All of these drugs have untoward side effects or require painful administration such as the intercavernous or intrauerethral injection of papaverine and PGE2. Natural product options widen the approaches. Nitric oxide, cAMP and cGMP messengers, smooth muscle adrenergic receptors, dopaminergic neurotransmitters and PGE-2 or other hormones are pharmacologic targets for impotence and low libido, which is complicated by psychosocial factors.